1. Field of Invention
This invention relates generally to the field of derivatized polyurethane polymers for in vitro and in vivo use.
2. Description of Related Art
Polyurethanes are polymers, which can be made by condensing a diisocyanate with a diol, with two or more diols having different structures, or with a diol and a diamine.
Medical grade segmented polyurethanes are usually prepared by condensing a diisocyanate with a polymeric diol having a molecular weight of about 1,000 to 3,000 (e.g., polytetramethyleneoxide for polyether-urethanes or polycarbonatediols for polycarbonate-urethanes) in order to form a polyurethane precursor which is subsequently reacted with an approximately equivalent amount of a chain extender (e.g., a diol such as 1,4-butanediol or a diamine such as a mixture of diaminocyclohexane isomers).
Polyurethanes can be used to form bulk polymers, coatings, fillings, and films. Once set, polyurethanes are also readily machinable. Polyurethanes were used for medical and non-medical purposes since at least the beginning of the twentieth century.
One type of medical application of polyurethanes involves a covalent immobilization of various proteins, cells, antibodies, and/or enzymes onto a polyurethane surface to make modified polyurethanes. Such modified polyurethanes would be useful in tissue engineering and artificial organ concepts, wound dressings, and gene delivery systems by making virtually any surgical implant and interventional device potentially therapeutic.
Surface coatings and treatments, however, are problematic in that they can invoke acute or chronic inflammatory responses to the coatings themselves. The use of synthetic polymers and biopolymer coatings for delivery purposes can, in some instances, result in an undesirable hyper-proliferation response among cells that contact the polymeric material. Polyurethane, poly(dimethyl siloxane) and polyethylene terephthalate coated stents are known to cause inflammation and thrombus formation. Low molecular weight poly-L-lactic acid coatings also cause an inflammatory response. Lincoff et al., J. Am. Coll. Cardiol., 29, 808.16 (1997).
Prior art polyurethanes that are suitably modified for the covalent immobilization of various proteins are rather limited in number and utility. For example, polyurethanes containing pendant carboxy groups were synthesized in order to covalently attach recombinant hirudin (Phaneuff, M. D. et al. “Covalent Linkage of Recombinant Hirudin to a Novel ionic Poly(carbonate)urethane Polymer With Protein Binding Sites: Determination of Surface Antithrombin Activity,” Artif Organs 1998; 22:657-65). Alternatively, polyurethanes with pendant epoxy groups have been used for the covalent immobilization of collagen (Huang L. L. H. et al. “Comparison of Epoxides on Grafting Collagen to Polyurethane and Their Effects on Cellular Growth,” J. Biomed. Mater. Res. 1998; 39:630-6).
One example of derivatizing polyurethanes with reactive moieties so such polyurethanes can react with molecules of interest, for example, bioactive molecules is polyurethane derivatized to contain pending geminal bisphosphonate groups disclosed in U.S. Pat. No. 6,320,011 to Levy et al. Derivatized polyurethane can then react with proteins, cells, antibodies, and/or enzymes.
Polyurethanes that are similarly modified with pendant thiol groups would be highly desirable and of more general utility than prior art polyurethanes. For example, polyurethanes having pendant thiol functionalities would be widely applicable for the conjugation of biologically active molecules such as proteins and would be very reactive in physiological environments. A significant challenge in preparing macromolecules that contain multiple thiol groups, however, lies in the unavoidable oxidative cross-linking of such macromolecules and subsequent reduction or loss of certain characteristics such as flexibility.
Therefore, despite there is a need for polyurethanes containing pendant thiol groups, which can be employed in a vast array of thiol-mediated biochemical interactions. Additionally, a need exists for methods of making such polyurethanes, which methods circumvent oxidative cross-linking of polymer molecules.
All references cited herein are incorporated herein by reference in their entireties.